Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• the present invention relates to an isothiourea derivative and pharmaceutical use thereof. More particularly, the present invention relates to an isothiourea derivative which has an amyloid- ⁇ (hereinafter referred to as ⁇ ) protein production inhibitory effect or a beta-site amyloid- ⁇ precursor protein cleavage enzyme 1 (hereinafter referred to as BACEl or beta-secretase) inhibitory effect and which may be effective for treating a neurodegenerative disease caused by ⁇ protein, in particular, Alzheimer' s-type dementia (AD), Down's syndrome or the like, and to a pharmaceutical composition comprising the isothiourea derivative as an active ingredient.
• ⁇ amyloid- ⁇
• BACEl or beta-secretase beta-secretase
• Alzheimer's disease is characterized by degeneration and loss of neurons as well as formation of senile plaques and neurofibrillary tangles.
• a symptom-improving agent typified by an acetylcholinesterase inhibitor, and a fundamental remedy to inhibit progression of the disease has not yet been developed. It is necessary to develop a method for controlling the causative pathology in order to create a fundamental remedy for Alzheimer's disease.
• ⁇ -proteins as breakdown products of amyloid precursor proteins (hereinafter referred to as APP) are critical to the degeneration and loss of neurons and onset of symptoms of dementia.
• ⁇ -proteins have, as main components, ⁇ 40 consisting of 40 amino acids and ⁇ 42 consisting of 42 amino acids wherein the two additional amino acids are present at the C-terminal.
• the ⁇ 40 and ⁇ 42 proteins are known to be highly prone to aggregation and to be the main components of the senile plaques linked to AD (Tanzi & Bertram, Cell 2005, 120: 545-555; Haass & Selkoe, Nat Rev Mol Cell Biol 2007, 8: 101-112).
• ⁇ 42 production providing further support that genetic mutations in APP which increase its processing by BACEl result in increased amyloid production and AD.
• a K670N/M671L double mutant (Swedish mutation), which has previously been shown to be linked to early onset AD (Mullan et al Nat Genet. 1992 1(5), Aug, 345-347) produced even more pronounced increases in ⁇ production than the A693V mutant.
• a compound that reduces production of ⁇ 40 and ⁇ 42 is predicted to be a disease progression inhibitor or prophylactic agent for Alzheimer' s- type dementia (AD).
• AD Alzheimer' s- type dementia
• AD Alzheimer's-type dementia
• ⁇ 40 and ⁇ 42 amyloidogenic conditions
• ⁇ deposition may be a causative factor in cognitive impairment associated with Down's syndrome.
• diabetes Another common co-morbidity in Down's syndrome is diabetes, being seven times more likely in individuals with Down's syndrome than the general population, and this increased frequency may be attributed to a gene product of chromosome 21, the triplication of all or some of which is
• BACE2 inhibitors may be useful for the treatment of diabetes (Esterhazy et al, Cell Metab., 2011, 14: 365-377). Accordingly, a dual BACE 1/2 inhibitor may provide an effective treatment for amyloid pathology and diabetes in the general or Down's syndrome populations.
• Examples of other neurodegenerative diseases that might be treatable or preventable with a compound that reduces progression of ⁇ 40 and ⁇ 42 include cerebrovascular amyloid angiopathy (CAA), mild cognitive impairment (MCI), memory loss, presenile dementia, senile dementia, hereditary cerebral hemorrhage with amyloidosis, and other degenerative dementias such as dementias of mixed vascular and degenerative origin, dementia associated with supranuclear palsy, dementia associated with cortical basal degeneration, dementia associated with Parkinson's Disease (PD), and dementia associated with diffuse Lewy Body type of AD.
• CAA cerebrovascular amyloid angiopathy
• MCI mild cognitive impairment
• MCI mild cognitive impairment
• memory loss presenile dementia
• senile dementia hereditary cerebral hemorrhage with amyloidosis
• other degenerative dementias such as dementias of mixed vascular and degenerative origin, dementia associated with supranuclear palsy, dementia associated with cortical basal degeneration, dementia associated with
• CJD Creutzfield- Jakob Disease
• peripheral nerve injury peripheral neuropathy, progressive supra-nuclear palsy, stroke
• amyotrophic lateral sclerosis ALS
• autoimmune diseases inflammation, arterial thrombosis, anxiety disorders, psychotic disorders, epilepsy, seizures, convulsions, stress disorders, vascular amyloidosis, pain, Gerstmann-Straeussler-Scheinker syndrome, scrapie, encephalopathy
• Whipple's Disease Kostmann Disease, glaucoma, hereditary cerebral hemorrhage with amyloidosis, cerebral hemorrhage with amyloidosis, vascular amyloidosis, brain inflammation, fragile X syndrome, stroke, Tourette's syndrome, inclusion body myositis, stress disorders, depression, bipolar disorder and obsessive compulsive disorder.
• BACE1 inhibitors may also be useful in a therapeutic approach to accelerate
• ⁇ is produced by the cleavage of APP by beta-secretase (BACE1) and subsequently by gamma-secretase. For this reason, attempts have been made to create compounds which inhibit ⁇ production. Examples of compounds having an ⁇ or
• BACE 1 inhibitory effect are described for example in WO2011009897,
• WO2009097278 Several ⁇ inhibitors have been investigated in clinical studies as potential treatments for AD.
• the compound MK-8931 has been reported to reduce CSF ⁇ 40, ⁇ 42 and ⁇ in AD patients (Forman et al, 11 th International Conference on Alzheimer's & Parkinson's Diseases, Florence, Italy, 7th March 2013).
• Other examples include LY2811376 (J. Neurosci 2011, Vol. 31(46): 16507-16516) and LY2886721 (May et al., 11 th International Conference on Alzheimer's & Parkinson's Diseases, Florence, Italy, 7th March 2013).
• BBB blood brain barrier
• transporters Hitchcock and Pennington, J. Med. Chem. 2006, 29, 7559; Ueno, Curr. Med. Chem. 2007, 14, 1199; Gloor et al, Brain Res. Rev. 2001, 36, 258.
• Several efflux transporters have been characterised which prevent compounds entering the brain.
• Pgp P-glycoprotein
• An object of the present invention is to provide compounds that have an ⁇ production inhibitory effect or a BACE1 inhibitory effect and which may be useful as prophylactic or therapeutic agents for a neurodegenerative disease caused by ⁇ and typified by Alzheimer-type dementia (AD) or Down's syndrome.
• AD Alzheimer-type dementia
• the invention provides a compound of formula (I):
• Pv 1 is a 5- to 10- membered carbocyclic group or a 5- to 10- membered
• heterocyclic group either of which is optionally substituted with at least one substituent independently selected from a halogen atom, a cyano group, a nitro group, a hydroxyl group, a carbamoyl group which is optionally substituted with one or two Ci_ 6 alkyl groups, a sulfonylamino group which is optionally substituted with one or two Ci_ 6 alkyl groups, an aminosulfonyl group which is optionally substituted with one or two Ci_ 6 alkyl groups, an amino group which is optionally substituted with one or two Ci_ 6 alkyl groups which are each optionally substituted with 1 to 3 substituents selected from Substituent Group a, a C 2 -6 alkenyl group which is optionally substituted with 1 to 3 substituents selected from Substituent Group a, a C 2 _ 6 alkynyl group which is optionally substituted with 1 to 3 substituents selected from Substituent Group a, a Ci_ 6
• R is a 5- to 6- membered heteroaryl group optionally substituted with at least one substituent independently selected from a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group which is optionally substituted with one or two Ci_6 alkyl groups, a Ci_ 6 alkoxy group which is optionally substituted with 1 to 3 substituents selected from Substituent Group a, and a Ci_ 6 alkyl group which is optionally substituted with 1 to 3 substituents selected from Substituent Group a;
• R 3 and R 4 each independently represent a hydrogen atom, a C3-6 cycloalkyl group or a Ci_ 6 alkyl group optionally substituted with 1 to 3 substituents selected from Substituent Group a;
• each substituent selected from Substituent Group a is independently a halogen atom, a cyano group, a hydroxyl group, a Ci_ 6 alkoxy group or an oxo group;
• R 5 is a hydrogen atom or a fluorine atom
• R 6 , R 7 , R 8 and R 9 are independently a hydrogen atom, a methyl group, a monofluoromethyl group, a difluoromethyl group or a trifluoromethyl group.
• the isothiourea derivative of formula (I) or pharmaceutically acceptable salt thereof according to the present invention may be a solvate thereof.
• a solvate include a hydrate.
• R is a 5- to 6- membered nitrogen- containing heteroaryl group optionally substituted with at least one substituent independently selected from a halogen atom, a Ci- 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci-6 haloalkoxy group, a Ci_ 6 hydroxyalkyl group and a Ci- 6 alkyl group which is optionally substituted with a Ci_ 6 alkoxy group.
• R is a 5- to 6- membered nitrogen- containing heteroaryl group substituted with at least one substituent independently selected from a halogen atom, a Ci- 6 haloalkyl group, a Ci- 6 alkyl group and a Ci_ 6 alkoxy group.
• R is a group of formula (II),
• R , R and R are independently a hydrogen atom, a halogen atom, a Ci- 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci- 6 haloalkoxy group, a Ci_ 6 hydroxyalkyl group or a C 1-6 alkyl group optionally substituted with a Ci- 6 alkoxy group.
• R 1 is a phenyl group, a pyridinyl group or a thienyl group, any of which is optionally substituted with at least one substituent independently selected from a halogen atom, a cyano group, a Ci_ 6 haloalkyl group, a Ci_6 alkoxy group, a Ci- 6 alkyl group which is optionally substituted with a Ci_ 6 alkoxy group, and an amino group which is optionally substituted with one or two substituents independently selected from a Ci_ 6 alkyl group and a Ci_ 6 haloalkyl group.
• R 1 is a phenyl group or thienyl group, either of which is optionally substituted with at least one substituent independently selected from a halogen atom, a Ci_ 6 haloalkyl group or a Ci_ 6 haloalkoxy group.
• R 1 is a phenyl group which is optionally substituted with at least one substituent independently selected from a fluorine atom, a chlorine atom, a cyano group, a Ci_ 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci- 6 alkyl group which is optionally substituted with a Ci_ 6 alkoxy group, and an amino group which is optionally substituted with one or two substituents independently selected from a Ci_6 alkyl group and a Ci_ 6 haloalkyl group.
• R 1 is a group of formula (III),
• R a is a hydrogen atom or a fluorine atom; and R is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a Ci_ 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci-6 alkyl group which is optionally substituted with a Ci_ 6 alkoxy group, or an amino group which is optionally substituted with one or two substituents independently selected from a Ci_ 6 alkyl group and a Ci_ 6 haloalkyl group.
• R 1 is a group of formula (III) wherein R 10a is a fluorine atom and R 10b is a hydrogen atom.
• R 1 is a group of formula (III), wherein R 10a is a hydrogen atom and R 10b is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a Ci_ 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci- 6 alkyl group which is optionally substituted with a Ci_ 6 alkoxy group, or an amino group which is optionally substituted with one or two substituents independently selected from a Ci_ 6 alkyl group and a Ci_ 6 haloalkyl group.
• R 10a is a hydrogen atom and R 10b is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a Ci_ 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci- 6 alkyl group which is optionally substituted with a Ci_ 6 alkoxy group, or an amino group which is optionally substituted with one or two substituent
• R is a pyridinyl group which is optionally substituted with at least one subsitituent independently selected from a fluorine atom, a chlorine atom, a cyano group, a Ci_ 6 haloalkyl group and a Ci- 6 alkyl group.
• R 1 is a group of formula (IV),
• R is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a Ci_ 6 haloalkyl group or a Ci- 6 alkyl group.
• R 1 is a cyclohexyl group or cyclopentyl group, either of which is optionally substituted with at least one substituent
• Ci_ 6 haloalkyl group independently selected from a halogen atom, a Ci_ 6 haloalkyl group or a Ci_ 6 haloalkoxy group.
• R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom.
• the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is a phenyl group or thienyl group, either of which is optionally substituted with at least one substituent
• R is a 5- to 6-membered nitrogen-containing heteroaryl group substituted with at least one substituent independently selected from a halogen atom, a Ci-6 haloalkyl group, a Ci- 6 alkyl group and a Ci_ 6 alkoxy group; and R 3 , R 4 , R 5 , R 6 , R 7 ,
• R and R are each independently a hydrogen atom.
• the present invention provides a compound of formula (IA)
• R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are defined as for formula (I);
• n is 1 or 2; and each R 10 is independently a fluorine atom, a chlorine atom, a cyano group, a Ci_ 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci- 6 alkyl group which is optionally substituted with a Ci_ 6 alkoxy group, or an amino group which is optionally substituted with one or two substituents independently selected from a Ci_ 6 alkyl group and a Ci_ 6 haloalkyl group.
• the invention provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently a fluorine atom.
• the present invention provides a compound of formula (IB)
• R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are defined as for Formula (I);
• n is 1 or 2; each R 10 is a fluorine atom, a chlorine atom, a cyano group, a Ci_ 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci- 6 alkyl group which is optionally substituted with a Ci_6 alkoxy group, or an amino group which is optionally substituted with one or two substituents independently selected from a Ci_ 6 alkyl group and a Ci_ 6 haloalkyl group; and
• R , R ⁇ and R 1J are independently selected from a hydrogen atom, a halogen atom, a Ci- 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci- 6 haloalkoxy group, a Ci_ 6 hydroxyalkyl group and a Ci- 6 alkyl group optionally substituted with a Ci- 6 alkoxy group.
• R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently a hydrogen atom.
• the present invention provides a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein each R 10 is fluorine; and R 11 , R 12
• R are independently selected from a hydrogen atom, a halogen atom, a Ci- 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci_ 6 hydroxyalkyl group and a Ci- 6 alkyl group optionally substituted with a Ci- 6 alkoxy group.
• the present invention provides a compound of formula (IB), or a pharmaceutically acceptable salt thereof, wherein
• R 11 is a Ci_6 alkoxy group
• R is a fluorine atom or a Ci- 6 haloalkyl group
• R is a hydrogen atom, a Ci_ 6 alkyl group, a Ci_ 6 haloalkyl group or a Ci_ 6 hydroxyalkyl group.
• the present invention provides a compound of formula (IBa),
• R is a hydrogen atom, a fluorine atom or a cyano group
• R 11 is a methoxy group
• R 12 is a hydrogen atom or a fluorine atom
• R 13 is a hydrogen atom, a methyl group, a monof uoromethyl group, a difluoromethyl group or a hydroxymethyl group.
• the present invention provides a compound of formula (IC)
• R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are defined as for formula (I);
• X 1 and X" are independently selected from a bond, methylene (-CH 2 -) and ethylene (-CH 2 CH 2 )-;
• A is methylene (-CH 2 -) or an oxygen atom.
• the present invention provides a compound of formula (ID)
• R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are defined as for Formula (I);
• A is methylene (-CH 2 -) or an oxygen atom
• X 1 and X" are independently selected from a bond, methylene (-CH 2 -) and ethylene (-CH 2 CH 2 )-;
• R II , R 1 ⁇ 2 and R 1 1 3 J are independently selected from a hydrogen atom, a halogen atom, a Ci- 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci- 6 haloalkoxy group, a Ci_ 6 hydroxyalkyl group and a Ci- 6 alkyl group optionally substituted with a Ci- 6 alkoxy group.
• the present invention provides a compound of formula (ID) wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 are each independently a hydrogen atom.
• the present invention provides a compound of formula (ID), or a pharmaceutically acceptable salt thereof, wherein
• R 11 is a Ci_6 alkoxy group
• R is a fluorine atom or a Ci- 6 haloalkyl group
• R is a hydrogen atom, a Ci_ 6 alkyl group, a Ci_ 6 haloalkyl group or a Ci_ 6 hydroxyalkyl group.
• the present invention provides a compound of formula (IE)
• R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are defined as for formula (I);
• n is 0 or 1;
• R 10 is a fluorine atom, a chlorine atom, a cyano group, a Ci_ 6 haloalkyl group or a Ci- 6 alkyl group.;
• R 11 , R 1 l 2 z and R 1 1 3 J are independently selected from a hydrogen atom, a halogen atom, a Ci- 6 haloalkyl group, a Ci_ 6 alkoxy group, a Ci- 6 haloalkoxy group, a Ci_ 6 hydroxyalkyl group and a Ci- 6 alkyl group optionally substituted with a Ci- 6 alkoxy group.
• the present invention provides a compound of formula (IE) wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 are each independently a hydrogen atom.
• the present invention provides a compound of formula (IEa), or a pharmaceutically acceptable salt thereof,
• R 10 is a hydrogen atom, a fluorine atom or a trifluoromethyl group
• R 11 is a methoxy group
• R is a hydrogen atom or a fluorine atom
• R is a hydrogen atom, a methyl group, a monofluoromethyl group, a difluoromethyl group or a hydroxymethyl group.
• the compounds of formula (I) comprise chiral centers located at the 7a and 4a positions as depicted below.
• the compounds of formula (I) may be present either in a stereochemically pure form or as a mixture with one or more of the other possible stereoisomers, for example in a racemic mixture or diastereomeric mixture.
• the present invention provides a compound of formula (I) selected from:-
• the present invention provides a compound of formula (I) selected from:-
• the present invention provides the compound
• the present invention provides the compound
• the present invention provides the compound
• Ci_ 6 alkyl refers to an alkyl group having 1 to 6 carbon atoms.
• examples of the group include linear and branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylpropyl, 1 ,2-dimethylpropyl, 1-ethylpropyl, l-methyl-2- ethylpropyl, l-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1 -methylbutyl, 2- methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2- methylpentyl and 3-methylpentyl.
• C2- 6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms.
• Examples of the group include linear and branched alkenyl groups such as vinyl, allyl, 1-propenyl, isopropenyl, 1-buten-l-yl, l-buten-2-yl, l-buten-3-yl, 2- buten-l-yl and 2-buten-2-yl.
• C2- 6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms.
• Examples of the group include linear and branched alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl and hexynyl.
• halogen refers to fluorine, chlorine, bromine or iodine.
• Ci_ 6 haloalkyl' denotes a Ci_ 6 alkyl group substituted with one to three halogen atoms wherein each halogen is independently selected from fluorine, chlorine, bromine and iodine.
• Ci_ 6 haloalkyl groups include CF 3 (trif uoromethyl), CHF 2 (difluoromethyl), CH 2 F (monofluoromethyl), CH 2 CF ,
• Ci_ 6 hydroxyalkyl denotes a Ci_ 6 alkyl group substituted with one to three hydroxyl groups.
• Examples of Ci_ 6 hydroxyalkyl groups include -CH 2 OH (hydroxymethyl).
• Examples of a "Ci_ 6 alkoxy” group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, sec- pentoxy, t-pentoxy, n-hexyloxy, isohexyloxy, 1,2-dimethylpropoxy, 2-ethylpropoxy, 1- methyl-2-ethylpropoxy, l-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,1- dimethylbutoxy, 2,2-dimethylbutoxy, 2-ethylbutoxy, 1,3-dimethylbutoxy, 2- methylpentoxy, 3-methylpentoxy and hexyloxy.
• Examples of a "Ci_ 6 haloalkoxy” group include -OCHF 2 (difluoromethoxy).
• Examples of a "Ci_ 6 alkylthio" group include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, t-butylthio, n-pentylthio, isopentylthio, neopentylthio, n-hexylthio and 1-methylpropylthio.
• Examples of an "amino"group optionally substituted with one or two substituents independently selected from a Ci_ 6 alkyl group and a Ci_ 6 haloalkyl group include amino (-NH 2 ), methylamino (-NHMe), ethylamino (-NHEt), dimethylamino (-NMe 2 ), diethylamino (-NEt 2 ) and bis(2-fluoroethyl)amino (-NHCH(CH 2 F) 2 .
• Examples of a "carbamoyl"group which is optionally substituted with one or two Ci_6 alkyl groups include -CONH 2 , -CONMe 2 and -CONEt 2 .
• Examples of a "sulfonylamino" group which is optionally substituted with one or two Ci_6 alkyl groups include methylsulfonylmethylamino (-N(Me)S0 2 Me).
• Examples of an "aminosulfonyl"group which is optionally substituted with one or two Ci_6 alkyl groups include -S0 2 NH 2 , -S0 2 NMe 2 and -S0 2 NEt 2 .
• the term "carbocyclic” denotes ring systems having 3 to 10 ring carbon atoms, including aryl rings, non-aromatic rings such as cycloalkyl rings and partially saturated rings, monocyclic rings and fused bicyclic rings including condensed, bridged and spirocyclic rings.
• cycloalkyl denotes saturated carbocyclic rings having 3 to 10 carbon atoms.
• aryl denotes aromatic carbocyclic rings having 6 to 10 carbon atoms, including monocyclic aromatic rings and fused bicyclic rings wherein both rings are aromatic.
• the term carbocyclic includes fused bicyclic rings wherein one ring is non-aromatic and the other is aromatic, e.g. indanyl. Examples of "cycloalkyl” rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
• cycloheptyl and cyclooctyl examples include phenyl and naphthyl.
• heterocyclic denotes ring systems having 5 to 10 ring atoms wherein at least one ring atom is selected from nitrogen, oxygen and sulphur, including heteroaryl rings, non-aromatic rings such as heterocycloalkyl rings and partially saturated rings, monocyclic rings and fused bicyclic rings including condensed, bridged and spirocyclic rings.
• heterocyclic also includes fused bicyclic rings containing at least one ring heteroatom wherein one ring is non-aromatic and the other is aromatic.
• heteroaryl denotes aromatic rings having 5 to 10 ring atoms wherein at least one ring atom is selected from nitrogen, oxygen and sulphur, including monocyclic aromatic rings and fused bicyclic rings wherein both rings are aromatic.
• 'heterocycloalkyl' denotes saturated rings having 5 to 10 ring atoms wherein at least one ring atom is selected from nitrogen, oxygen and sulphur.
• Examples of 5 to 6-membered "heteroaryl” groups include furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
• a group may be substituted or unsubstituted.
• the group may for example be unsubstituted or substituted with 1, 2 or 3 substituents.
• crystal polymorphs of the compound of formula (I) may be present, the compound is similarly not limited thereto and may be present as a single crystal form or a mixture of single crystal forms.
• the compound may be an anhydride or a hydrate. Any of these forms are included in the scope of the present invention.
• the present invention also includes isotopically-labelled compounds, which are identical to the compounds of formula (I), except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, phosphorous, chlorine, technetium and iodine, such as 2 H, 3 H, n C, 14 C, 13 N, 15 0, 18 F, 32 P, 99m Tc, 123 I and 131 I.
• Isotopically- labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and/or 14 C are incorporated, may be useful in drug and/or substrate tissue distribution assays due to their ease of preparation and detectability.
• U C, 15 0 and 18 F isotopes may be useful in PET (positron emission tomography), and 99m Tc, 123 I
• I isotopes may be useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Substitution with heavier isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be considered useful in some circumstances.
• Isotopically labelled compounds of formula (I) of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
• the isothiourea derivative of the formula (I) according to the present invention may be a pharmaceutically acceptable salt.
• Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
• the pharmaceutically acceptable salt include inorganic acid salts (such as sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydro fluorides, hydrochlorides, hydrobromides and hydroiodides), organic carboxylates (such as acetates, oxalates, maleates, tartrates, fumarates, citrates, malonates, lactates and hippurates), organic sulfonates (such as methanesulfonates,
• trifluoromethanesulfonates ethanesulfonates, benzenesulfonates, toluenesulfonates and camphorsulfonates
• amino acid salts such as aspartates and glutamates
• quaternary amine salts alkali metal salts (such as sodium salts and potassium salts) and alkali earth metal salts (such as magnesium salts and calcium salts).
• the compound of formula (I) according to the present invention may be converted to a pharmaceutically acceptable salt by a conventional method where necessary.
• the salt may be prepared by a method in which methods typically used in the field of organic synthetic chemistry and the like are appropriately combined.
• Specific examples of the method include neutralization titration of a free solution of the compound of the present invention with an acid solution.
• the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention may be converted to a solvate by subjecting the compound to a solvate forming reaction known per se where necessary.
• the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
• the isothiourea derivative or pharmaceutically acceptable salt thereof according to the present invention has an ⁇ production inhibitory effect and may be useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by ⁇ and typified by Alzheimer-type dementia.
• the compounds of the invention may reduce both ⁇ 40 and ⁇ 42.
• the compounds of the present invention may have a BACE 1 and a BACE 2 inhibitory effect.
• the present invention provides a compound of formula
• the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for inhibiting beta-site amyloid- ⁇ precursor protein cleaving enzyme 1 (BACE 1).
• BACE beta-site amyloid- ⁇ precursor protein cleaving enzyme 1
• the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for treating or preventing a neurodegenerative disease.
• the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for treating or preventing Alzheimer-type dementia (AD).
• the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for treating Down's syndrome.
• the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a neurodegenerative disease.
• the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of Alzheimer-type dementia (AD).
• AD Alzheimer-type dementia
• the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Down's syndrome.
• the invention provides a method of inhibiting production of amyloid- ⁇ protein involving administering to a human subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• Effective amount means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.
• the invention provides a method of treating or preventing Alzheimer-type dementia (AD) involving administering to a human subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• AD Alzheimer-type dementia
• the invention provides a method of treating Down's syndrome involving administering to a human subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention further provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for treating type 2 diabetes.
• the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of type 2 diabetes.
• the present invention further provides a method of treating or preventing type 2 diabetes involving administering to a human subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• a further aspect of the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, as active ingredient in association with a pharmaceutically acceptable carrier.
• the composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for
• the isothiourea derivative or pharmaceutically acceptable salt thereof according to the present invention may be formulated by a conventional method.
• the dosage form include tablets, coated tablets such as film tablets and sugar-coated tablets, fine granules, granules, powders, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye drops, nasal drops, ear drops, cataplasms and lotions.
• solid preparations such as tablets, capsules, granules and powders may contain generally 0.01 to 100 wt%, and preferably 0.1 to 100 wt% of the fused isothiourea derivative or pharmaceutically acceptable salt thereof according to the present invention as an active ingredient.
• the active ingredient is formulated by blending ingredients generally used as materials for a pharmaceutical preparation and adding an excipient, a disintegrant, a binder, a lubricant, a colorant and a corrective typically used, and adding a stabilizer, an emulsifier, an absorbefacient, a surfactant, a pH adjuster, a preservative and an antioxidant where necessary, for example, using a conventional method.
• ingredients include animal and vegetable oils such as soybean oil, beef tallow and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; a silicone resin; silicone oil; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil and a polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, a carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerol, propylene
• excipient used examples include lactose, corn starch, saccharose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide.
• binder used examples include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose,
• hydroxypropylcellulose polyvinylpyrrolidone, a polypropylene glycol-polyoxyethylene block copolymer and meglumine.
• disintegrant used include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and carboxymethylcellulose calcium.
• lubricant used include magnesium stearate, talc, polyethylene glycol, silica and hydrogenated vegetable oil.
• the colorant used include those permitted to be added to pharmaceuticals.
• Examples of the corrective used include cocoa powder, menthol, empasm, mentha oil, borneol and cinnamon powder. Obviously, the ingredients are not limited to the above additive ingredients.
• an oral preparation is prepared by adding the fused isothiourea derivative or pharmaceutically acceptable salt thereof according to the present invention as an active ingredient, an excipient and, where necessary, a binder, a disintegrant, a lubricant, a colorant, a corrective and the like, and then forming the mixture into powder, fine granules, granules, tablets, coated tablets, capsules or the like by a conventional method.
• tablets or granules may be appropriately coated, for example, sugar coated, where necessary.
• a syrup or an injection preparation is prepared by adding a pH adjuster, a solubilizer, an isotonizing agent and the like, and a solubilizing agent, a stabilizer and the like where necessary by a conventional method.
• the injection may be a previously prepared solution, or may be powder itself or powder containing a suitable additive, which is dissolved before use.
• the injection may contain usually 0.01 to 100 wt%, and preferably 0.1 to 100 wt% of the active ingredient.
• a liquid preparation for oral administration such as a suspension or a syrup may contain usually 0.01 to 100 wt%, and preferably 0.1 to 100 wt% of the active ingredient.
• an external preparation may be prepared by any conventional method without specific limitations.
• a base material any of various materials usually used for a pharmaceutical, a quasi drug, a cosmetic or the like can be used.
• the base material examples include materials such as animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and purified water.
• a pH adjuster, an antioxidant, a chelator, a preservative and fungicide, a colorant, a flavor or the like can be added where necessary.
• ingredients such as an ingredient having a differentiation inducing effect, a blood flow enhancer, a bactericide, an antiphlogistic, a cell activator, vitamin, amino acid, a humectant and a keratolytic agent can be blended where necessary.
• the dose of the isothiourea derivative or pharmaceutically acceptable salt thereof according to the present invention may vary according to the degree of symptoms, age, sex, body weight, mode of administration, type of salt and specific type of disease, for example.
• the active ingredient is orally administered to an adult at about 30 ⁇ g to 10 g, preferably 100 ⁇ g to 5 g, and more preferably 100 ⁇ g to 1 g per day, or is administered to an adult by injection at about 30 ⁇ g to 1 g, preferably 100 ⁇ g to 500 mg, and more preferably 100 ⁇ g to 300 mg per day, in one or several doses, respectively.
• the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further active ingredient useful in treating a neurodegenerative disease.
• the neurodegenerative disease is Alzheimer-type dementia (AD).
• Suitable examples of such further active ingredients may be symptomatic agents, for example those known to modify cholinergic transmission such as Ml and M3 muscarinic receptor agonists or allosteric modulators, M2 muscarinic antagonists, M4 agonists or positive allosteric modulators (PAMs), acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), nicotinic receptor agonists or allosteric modulators (such as a7 agonists or allosteric modulators or ⁇ 4 ⁇ 2 agonists or allosteric modulators), PPAR agonists (such as PPARy agonists), 5-HT 4 receptor agonists or partial agonists, histamine H3 antagonists, 5-HT 6 receptor antagonists or 5HTIA receptor ligands and NMD A receptor antagonists or modulators (such as memantine), 5- HT 2 A antagonists, 5-HT 7
• phosphorylation/kinase inhibitors tau dephosphorylation / phosphatase activators, mitogen-activated protein kinase kinase 4 (MKK4/MEK4/MAP2K4) inhibitors, c-Jun
• JNK N-terminal kinase
• casein kinase inhibitors MK2 (mitogen activated protein kinase-activated protein kinase 2) inhibitors, MARK (microtubule affinity regulating kinase) inhibitors, CDK5 (cyclin dependent kinase 5) inhibitors, GSK-3 (glycogen synthase kinase-3) inhibitors and tau-tubulin kinase-1 (TTBK1) inhibitors.
• Such other therapeutic agents may be calcium channel blockers, HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) and lipid lowering agents, NGF (nerve growth factor) mimics, antioxidants, GPR3 ligands, plasmin activators, neprilysin (NEP) activators, IDE (insulin degrading enzyme) activators, melatonin MT1 and/or MT2 agonists, TLX/NR2E1 (tailless X receptor) ligands, GluRl ligands, RAGE (receptor for advanced glycation end-products) antagonists, EGFR (epidermal growth factor receptor) inhibitors, FPRL-1 (formyl peptide-like receptor- 1) ligands, GAB A antagonists, and MICAL (molecule interacting with casL) inhibitors, e.g.
• HMG-CoA 3-hydroxy-3-methyl-glutaryl-CoA reduct
• oxoreductase inhibitors CB1 antagonists/inverse agonists, non-steroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory agents (for example agents that could be used to treat neuroinflammation either by enhancing or reducing neuroinflammation), amyloid precursor protein (APP) ligands, anti-amyloid vaccines and / or antibodies, agents that promote or enhance amyloid efflux and / or clearance, histone deacetylase (HDAC) inhbitors, EP2 antagonists, 11 -beta HSD1 (hydroxysteroid dehydrogenase) inhibitors, liver X receptor (LXR) agonists or PAMs, lipoprotein receptor-related protein (LRP) mimics and / or ligands and/or enhancers and/or inhibitors, butyryl cholinesterase inhibitors, kynurinic acid antagonists and / or inhibitors of kynurenine aminotransferease (KAT), orphanin FQ / nociceptin (
• the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further active ingredient selected from:-
• cholinesterase inhibitors e.g. donepezil, galantamine, rivastigamine
• NMDA receptor antagonists e.g. memantine and pharmaceutically acceptable salts thereof, and any other compounds which elicit their effects by a similar mechanism of action
• 5-HT 6 antagonists e.g. SB-742457 and pharmaceutically acceptable salts thereof
• HMGCoA reductase inhibitors e.g. lovastatin, rosuvastatin, atorvastatin,
• simvastatin simvastatin, fluvastatin, pitavastatin, pravastatin and pharmaceutically
• the pharmaceutical product may, for example be a pharmaceutical composition comprising the first and further active ingredients in admixture.
• the pharmaceutical product may for example comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof.
• compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
• each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
• an additional aspect of the invention provides a method of preparing a pharmaceutical composition, involving admixing at least one compound of formula (I) as defined above, or a pharmaceutically acceptable salt therof, with one or more pharmaceutically acceptable adjuvants, diluents or carriers and/or with one or more other therapeutically or prophylactically active agents.
• the choice of solvent for a particular reaction is not particularly limited in so far as it will not inhibit the reaction, is compatible with the reactants and will allow the starting material to be dissolved to a certain extent. Further, reaction temperatures and reaction time may be varied according to the starting material, the reagent used and the like. As will be understood by those skilled in the art, when preparing certain compounds of formula (I) it may be appropriate to modify the following Preparation Methods by alternating the sequence of reaction steps and/or incorporating additional steps to vary substituent groups on intermediate compounds. Moreover, it will also be recognised that compounds of formula (I) prepared according to the General Preparation Methods may subsequently be converted to other compounds of formula (I) using known chemistry.
• Diazabicycloundec-7-ene DBU; dichloromethane (DCM); 2,4,-dimethoxybenzyl (DMPM); ⁇ , ⁇ -Dimethylacetamide (DMA); ⁇ , ⁇ -Dimethylformamide (DMF); N, N- diisopropylethylamine (DIPEA); 4-methoxybenzyl (MPM); N-Methyl-2-pyrrolidone (NMP); mesyl (Ms); tetrahydrofuran (THF); triethylamine (TEA); trifluoroacetic acid (TFA); triflyl (Tf); Teoc (2-trimethylsilylethyl carbamate); tosyl (Ts).
• DBU dichloromethane
• DMPM 2,4,-dimethoxybenzyl
• DMA ⁇ , ⁇ -Dimethylacetamide
• DMF ⁇ , ⁇ -Dimethylformamide
• DIPEA N- diisopropy
• Suitable conditions for the preparation of lb from la include addition of an organometallic reagent (R M) to la in a suitable solvent, such as THF, PhMe, Et 2 0 and the like, in the presence or absence of a Lewis Acid, for example BF 3 OEt 2 .
• Suitable organometallic reagents include organo lithium and Grignard reagents.
• the reaction temperature may for example be in the range -78°C to room temperature, preferably less than 0°C.
• the reaction time will vary based on the reagents used but those skilled in the art will be able to monitor the progress of the reaction and thereby judge the optimal reaction time.
• Suitable conditions to prepare lc from lb include Zn in acetic acid or mixed solvent systems which include acetic acid in addition to organic solvents that do not interfere with the reaction, for example THF.
• the reaction temperature may for example be in the range 0°C to solvent reflux, typically 0°C to room temperature.
• the reaction time may typically vary from 0.5 hours to 24 hours.
• Suitable conditions to convert lc to Id include reaction with
• reaction temperature may for example be in the range -78°C to room temperature.
• reaction time may vary from 5 minutes to 24 hours.
• Suitable conditions to convert Id to le include reaction with triflic anhydride in a suitable solvent, such as DCM, in the presence of a base, such as pyridine.
• a suitable solvent such as DCM
• the reaction temperature may for example be in the range -78°C to room temperature, typically -20°C to 0°C.
• the reaction time may vary from 5 minutes to 24 hours.
• Suitable conditions to convert le to If include those described in reference 1.
• MCM 4-methoxybenzyl
• Suitable conditions to convert If to lg include transition metal (e.g. Pd) catalysed coupling reactions
• suitable conditions include those described by Buchwald (for example Chemical Science, 2011, 2(1), 27-50; Chemical Science, 2011, 2(1), 57- 68).
• Particular conditions include Pd(OAc) 2 as palladium source or precatalyst, NaOt- Bu as a base, t-BuDavePhos as ligand for palladium, dioxane as solvent and reaction temperature 120°C.
• the reaction temperature may for example be in the range room temperature to solvent reflux, and the reaction time from 5 minutes to 1 week.
• the same transformation may be effected by treating If with a base such a triethylamine and the like in a solvent, such as acetonitrile or NMP.
• a base such as triethylamine and the like in a solvent, such as acetonitrile or NMP.
• the reaction can be performed under microwave conditions in the range 80°C to 150°C, and reaction time from 0.5 to 24 hours.
• a base such as DBU
• This reaction can be performed under the same conditions as those described in Synth. Commun. 2002, 32 (2), 265-272, for example.
• the reaction can be performed using 1 equivalent to a large excess of base.
• the reaction temperature is usually room temperature to solvent reflux temperature.
• the reaction time is usually 0.5 to 24 hours.
• a base such as K 2 CO 3
• the reaction can be performed using 1 equivalent to a large excess of base.
• the reaction temperature may for example be in the range 50°C to 100°C, and the reaction time from 0.5 to 24 hours.
• alkyli denotes a suitable alkyl group (e.g. a Ci_ 6 alkyl group such Me, Et, Pr, Bu, z ' -Pr, i- Bu or t-Bu).
• a Ci_ 6 alkyl group such Me, Et, Pr, Bu, z ' -Pr, i- Bu or t-Bu.
• General Preparation Method 3 may be used to prepare compounds of formula (I) according to the present invention wherein R is a pyrimidinyl group of formula (II) as described herein above, from intermediates such as If (Scheme 3).
• W 1 denotes a suitable alkyl group (e.g. a Ci_ 6 alkyl group such Me, Et, Pr, Bu, z ' -Pr, z ' -Bu, t-
• Pyrrolidine derivative If can be prepared as described in General Preparation Method 1 and can be converted to the corresponding guanidine 3a (Step 3.1) by reaction with reagents such as 1-pyrazolecarboxamidine (lH-pyrazole-l-carboximidamide).
• the reaction temperature may for example be in the range 0°C to solvent reflux temperature, typically room temperature.
• the reaction time may vary from 5 minutes to 24 hours, typically 1 - 12 hours.
• the reaction solvent is not limited as long as it does not interfere with the reaction. Suitable solvents include DMF, DMA, NMP and the like.
• reaction may require a non-nucleophilic bases, for example TEA, DIPEA or diisopropylamine as 1-pyrazolecarboxamidine is generally used as a hydrochloride salt.
• a non-nucleophilic bases for example TEA, DIPEA or diisopropylamine
• alternative reagents may be used in place of 1-pyrazolecarboxamidine and that such reagents may deliver a protected guanidine analogue of 3a.
• Those skilled in the art will be able to select appropriate reagents and be able to effect the deprotection, if required at the appropriate stage.
• Compound 3a can be condensed with either diketone derivatives 3f or with beta- ketoester derivatives 3g to give compounds such as 3b or 3c, respectively, as depicted in Step 3.2 and Step 3.4.
• the reaction temperature may for example be in the range 0°C to solvent reflux temperature, typically reflux.
• the reaction time may vary from 5 minutes to 24 hours, typically 1 - 12 hours.
• Compounds 3f and 3g are commercially available or can be prepared by those skilled in the art.
• Compounds such as 3c can be further functionalised by alkylation to give derivatives 3d under standard conditions as depicted in Step 3.5, whereby LG is a leaving group such as halogen (CI, Br, I) or OTf, OMs, OTs or the like and W is for example a Ci_ 6 alkyl.
• LG is a leaving group such as halogen (CI, Br, I) or OTf, OMs, OTs or the like and W is for example a Ci_ 6 alkyl.
• 3c may be converted to 3e (Step 3.7) wherein LG 1 is a leaving group such as halogen (CI, Br, I), for example by treatment with POCI 3 , or LG 1 is OTf, OTs or OMs.
• LG 1 is a leaving group such as halogen (CI, Br, I), for example by treatment with POCI 3 , or LG 1 is OTf, OTs or OMs.
• Compound 3e can then be reacted with nucleophiles (Step 3.8) to give
• nucleophiles examples include alcohols, amines and carbon nucleophiles such as boronic acids and stannanes and the like. Those skilled in the art will appreciate that when a carbon nucleophile is used then a transition metal catalyst will be required, for example a Pd catalyst.
• Intermediate la can be prepared as shown in Scheme 4.
• Pi and alkyli are as defined in Scheme 1; W is as defined in Scheme 3, alkyl 2 is a suitable alkyl group (e.g. a Ci_ 6 alkyl group such Me, Et, Pr, Bu, z ' -Pr, z ' -Bu or t-Bu) and LG is a suitable leaving group (e.g. halogen (CI, Br, I), OTf, OMs OSu or OTs). Additionally, where there are two alkyl 2 groups present in a compound these groups may form a ring.
• a suitable alkyl group e.g. a Ci_ 6 alkyl group such Me, Et, Pr, Bu, z ' -Pr, z ' -Bu or t-Bu
• LG is a suitable leaving group (e.g. halogen (CI, Br, I), OTf, OMs OSu or OTs).
• Conditions to form these protected intermediates include those described in Reference 1.
• Pi is MPM or DMPM the protecting groups can be added as described in Reference 1, p. 581, or by reductive alkylation using 4-methoxybenzaldehyde or 2,4-dimethoxybenzaldehyde.
• the steps depicted in Scheme 4 involve chemistry that will be known to those skilled in the art. Further details can be found in references 3 and 4. Additional information on how certain reaction steps in Scheme 4 may conveniently be performed are provided herein below.
• Compounds 4f are either commercially available or may be prepared by incorporation of a protecting group Pi as outlined above. 4f can be reacted with allyl bromide, 4e, as in Step 4.4 to give compounds such as 4d.
• the reaction temperature may for example be in the range -20°C to 0°C and the reaction time may vary from 5 minutes to 24 hours, typically 1 - 12 hours.
• the reaction solvent is not limited as long as it does not interfere with the reaction. Suitable solvents include DMF, DMA, NMP and the like.
• reaction temperature may for example be in the range -78°C to 0°C and the reaction time may vary from 5 minutes to 24 hours, typically 1 - 12 hours.
• Step 4.7 Hydroxyimine formation
• the reaction temperature may for example be in the range room temperature to solvent reflux, typically reflux and the reaction time may vary from 5 minutes to 24 hours, typically 1 - 12 hours to give 4k.
• Cyclisation of 4k using NaOCl as in Step 4.8 affords intermediate la.
• intermediate 4c can be prepared via a different synthetic sequence.
• N-alkylation of allylamine 4a with bromoacetate 4b (step 4.1) can give access to N- allylglycine derivative 4c followed by subsequent protection with PiLG (step 4.2).
• Suitable conditions to convert 4a to 4c can be accomplished in a suitable solvent such as diethyl ether, tetrahydrofuran, or the like. This reaction can be performed under the same conditions as those described in Carbohydrate Research 2005, 340, 2457-2468 for example.
• the reaction temperature may for example be in the range 0°C to room temperature, and the reaction time from lh to 1 week.
• Suitable conditions to convert 4c to 4d include those described in reference 1.
• Aldehyde 4j may also be prepared from compound 41 which is first protected with PiLG (step 4.9).
• the resulting compound 4m can undergo alkylation with allyl bromide 4e to afford 4i (step 4.10), which may also be accessed from bromoacetal 4g.
• the acetal 4i can be converted into aldehyde 4j (step 4.10).
• Suitable conditions to convert 4i to 4j include those described in reference 1.
• Suitable conditions to convert 4m to 4i include use of base such as sodium hydride, cesium carbonate, or the like in a suitable solvent such as dimethylformamide, terahydrofuran, or the like.
• the reaction temperature may for example be in the range 0°C to room temperature, and the reaction time from lh to 1 week.
• Suitable conditions to convert 4i to 4j include use of acid such as formic acid, hydrogen chloride, or the like.
• the reaction temperature may for example be in the 0°C to room temperature, and the reaction time from lh to 1 week.
• intermediate lb may be prepared as outlined in Scheme 5.
• Pi and alkyli are as defined for Scheme 1 and LG is a suitable leaving group, (e.g. halogen (CI, Br, I) or OTf, OTs, OMs and the like).
• a suitable non-nucleophilic base for example TEA, DIPEA or diisopropylamine, is required as well as a suitable solvent such as DCM.
• This reaction affords the ketone derivative 5c and the reaction temperature may for example be in the range room temperature to solvent reflux, typically room temperature and the reaction time may vary from 5 minutes to 24 hours, typically 1 - 12 hours.
• Oxime formation (Step 5.6) can then be carried out using hydroxylamine hydrochloride in a suitable alcoholic solvent, e.g. in buffered or basic consitions.
• the reaction temperature may for example be in the range room temperature to solvent reflux, typically reflux and the reaction time may vary from 5 minutes to 24 hours, typically 1 - 12 hours to give 5h.
• compound 5c can be prepared from either compound 4d or commercialy available compound 5e in a three steps sequence, as depicted in Scheme 5.
• allyl amine 6b can be reacted with compounds 4g (Step 6.1).
• Suitable conditions include use of base such as sodium hydride, cesium carbonate, or the like in a suitable solvent such as dimethylformamide, tetrahydrofuran, or the like.
• the reaction temperature may for example be in the range 0°C to reflux, and the reaction time from lh to 1 week.
• the resulting acetal 6e could be converted into the aldehyde 6f and then to oxime 6g when treated with hydroxylamine hydrochloride in a suitable alcoholic solvent (step 6.9), e.g. in buffered conditions.
• the reaction temperature may for example be in the range 0°C to reflux, and the reaction time from lh to 1 week.
• the resulting acetal 6e could be converted into the aldehyde 6f and then to oxime 6g when treated with hydroxylamine hydrochloride in a suitable alcoholic solvent (step 6.9), e.g
• reaction temperature may for example be in the range room temperature to solvent reflux and the reaction time may vary from 5 minutes to 24 hours, typically 1 - 12 hours.
• 1,3-Dipolar cycloaddition reaction as in Step 6.10 is then achieved by conversion of 6g to a nitrile oxide derivative which reacst with the olefin moiety in the same molecule to afford the cyclic compound 2a.
• Suitable conditions include the use of N-chlorosuccinimide and sodium hypochlorite in a suitable solvent such as dichloromethane, chloroform, or the like.
• the reaction temperature may for example be in the range 0°C to solvent reflux temperature, and the reaction time from lh to 48 hours. This reaction can be performed under analogous conditions as those described as Org. Lett. 2007, 9, 753-756,
• Allyl amines of formula 6b may be prepared in one step from either allylamine or allylbromide following procedure as those described in Angew.Chem. Int. Ed.. 2011, 50, 5678-5681, JOC 2005, 70, 5164-5173 and Tet. Lett. 1998, 5P3131-3141.
• a general method of preparing compounds 6b wherein R is a pyrimidine, for example compound 9d, is described in Scheme 9.
• Compounds 4g are either commercially available or can be prepared by known chemistry.
• intermediate 2b may be prepared as outlined in Scheme 7.
• alkyli is as defined for Scheme 1
• LG is as defined for Scheme 4.
• the reactions and conditions depicted in Scheme 7 will be known to those skilled in the art. Further details can be found in references 3 and 4. Additional information on how certain reaction steps in Scheme 7 may conveniently be performed are provided herein below.
• allyl amine 6b can be reacted with derivatives of 5a (Step 7.1)
• Suitable conditions include use of base such as sodium hydride, or the like in a suitable solvent such as dimethylformamide, terahydrofuran, or the like.
• the reaction temperature may for example be in the range 0°C to reflux, and the reaction time from lh to 48h.
• the resulting ketone 7a can be converted to oxime 7b when treated with hydroxylamine hydrochloride in a suitable alcoholic solvent (step 7.2), e.g. in buffered conditions.
• the reaction temperature may for example be in the range room temperature to solvent reflux, typically reflux and the reaction time may vary from 5 minutes to 24 hours, typically 1 - 12 hours.
• intermediate 7a can be prepared via a different synthetic sequence.
• N-alkylation of allylamine 6b with either 2-chloro-N-methoxy-N-methylacetamide 7c can give the Weinreb amide derivative 7d or reaction with reagent of type 5e can give morpholinoethanone compound 7e (Step 7.4), in the presence of a base such as sodium hydride, or the like in a suitable solvent such as dimethylformamide, terahydrofuran, or the like. Subsequently both compounds 7d and 7e can be converted into compound 7a when treated with a suitable organometallic reagent (R x -M) (Step7.5).
• R x -M organometallic reagent
• N-( a -methylbenzyl)hydroxylamine may be used not only to deliver a diastereomeric product but also to influence the diastereomeric ratio.
• suitable Lewis acids include Ti(OEt)4.
• solvents THF THF.
• the reaction temperature may be in the range room temperature to solvent reflux, typically 50°C to 100°C.
• the reaction time may vary from 1 hour to 1 week.
• compounds 8b and 8d can be converted to derivatives such as lc (Schemel) and 2c (Scheme 2) respectively by reduction of the N-0 bond, for example by treatment with Zn in AcOH or
• Scheme 9 depicts several routes for preparing intermediate compounds that may be used in preparing Compounds of formula (I), wherein R is a pyrimidiyl group.
• R is as defined for formula (I)
• R , R are as defined for formula (II)
• W is as defined for Scheme 3
• alkyl 2 is as defined for Scheme 4 and W is, for example, a Ci_
• Allyl amine 4a may be converted to the corresponding guanidine 9b (as described in Scheme 9) which may then be condensed with a beta-ketoester derivative 3g to give pyrimidone derivative 9c. Selective O-alkylation may be achieved to give 9d which may then undergo further alkylation to give 9e. Compound 9e may then be transformed to Compound (I) via a similar sequence to that shown in Schemes 5, 6, 7 and 8.
• beta-ketoester derivative maybe replaced by a 1,3-diketone derivative such as 3f (Scheme 3). If 3f is used in place of 3g then similar reactions may be undertaken as those depicted in Scheme 3 and the resultant product maybe transformed to Compound (I) using similar reactions to those depicted in Schemes 5, 6,
• Alternative starting materials to 4a include, but are not limited to, 9a, 4c, 5b and 41 which are depicted in Scheme 9.
• the transformation of these starting materials may be accomplished as shown in Scheme 9 employing reaction conditions known to those skilled in the art.
• Compounds 9n and 9r may be transformed to Compound (I) using similar sequences to those described in Schemes 6, 7 and 8.
• AIBN Azobisisobutyronitrile
• BOC & Boc tert-butoxycarbonyl
• br broad
• Bn benzyl
• Bu butyl
• BuLi n-butyl lithium
• d doublet
• DBU 1,8- Diazabicyclo[5.4.0]undec-7-ene
• DCM dichloromethane
• dd doublet of doublets
• DIBAL disobutylaluminium hydride; DMF ( ⁇ , ⁇ -dimethylformamide); DMAP (4-N,N- dimethylaminopyridine); DMSO (dimethylsulfoxide); EDC & ED AC: (N-3(- dimethylaminopropyl)N'ethylcarbodiimide hydrochloride); Et: ethyl; Et20: diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; h, hr, hrs: hours; HCl: hydrochloric acid; HPLC: high performance liquid chromatography; LCMS, LC/MS & LC-MS: liquid chromatography / mass spectrometry; m: multiplet; Me: methyl; MeCN: acetonitrile; MeOH: methanol; MS: mass spectrometry; MDAP: mass directed auto purification; min & mins: minutes; NaOH: sodium hydroxide; NBS:
• designation as a mono hydrochloride salt may mean that the compound is a mono hydrochloride, a dihydrochloride, a trihydrochloride or that the stoichiometry of the hydrochloride to compound may may be anywhere from 0 - 3.
• G2 purified by column chromatography (normal phase, (1 lg/28g/55g/l 10g/375g), Biotage SNAP cartridge KP-NH, ( 12mL/25mL/5 OmL/ 1 OOmL) per min, gradient xx% to xx% EtOAc in n-hexane / MeOH in DCM).
• sample name/number solution containing 1.2mg (Sample name/number) in 1.2mL DCM
• chromatographic separation on the following 4 ChiralPAK® (i.d 4.6 mm x length 250 mm) chiral columns: IA (#1), IB (#2), IC (#3), and ID (#4).
• sample name/number x mg was dissolved in DCM (x mL), loaded into a vial (3.8 mL capacity) and subjected to chromatographic separation using preparative (column type) (i.d. 20 mm; length 250 mm) and (Solvent mixture) (v/v) as eluent.
• injection volume 1500 ⁇ Flow rate: 18.0 mL/min.
• Example 1 f ⁇ )-f4aR*,7aS*)-6-f5-Fluoro-4-methoxy-6-methylpyrimidin-2-yl)-7a-f2- fluorophenyl)-4,4a,5. l 6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2-amine l-(9)
• tert-butyl 3a,4- dihydro-3H-pyrrolo[3,4-c]isoxazole-5(6H)-carboxylate, i-(5), (20.3 g) was then added dropwise over 15 min as a solution in 100 mL THF, keeping the internal temperature below -72°C. After stirring at -78°C for a further 3h, the reaction was quenched by the addition of sat. aq. NH 4 CI (200 mL) and allowed to warm slowly to room temperature and stir overnight. Brine (200 mL) was then added and the mixture was extracted with
• Example 2 f ⁇ )-f4aR*,7aS*)-6-f5-fluoro-4-methoxypyrimidin-2-yl)-7a-f2- fluorophenyl)-4,4a,5. l 6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2-amine
• Example 3 ( ⁇ )-(4aR*.,7aS*)-6-( 5-fluoro-4-methoxy-6-( trifluoromethvDpyrimidin- 2-yl)-7a-(2-fluorophenyl)-4,4a,5,6J,7a-hexahvdropyrrolo [3,4-dl [ 1 ,31 thiazin-2- amine
• reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2 x 25 mL) then dried (MgS0 4 ) and evaporated. The residue was dissolved in dichloromethane and applied to a 10 g SNAP KP-Si column. Purified on the Biotage Isolera 4 eluting with 0 to 30% ethyl acetate / hexane over 10 column volumes to afford the title compound (0.06 g) as a white solid.
• Example 4 f ⁇ )-f4aR*,7aS*)-6-f5-fluoro-4-ffluoromethyl)-6-methoxypyrimidin-2- yl)-7a-f2-fluorophenyl)-4,4a,5.,6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2-amine
• Example 5 ( ⁇ )-( 4aR*,7aS*)-6-( 4-( difluorometh yl)-6-methoxypyrimidin-2-yl)-7a- fl-fluorophenvD ⁇ a ⁇ a-hexahvdropyrroloiS ⁇ -dl il ⁇ lthiazin-l-amine
• Example 6 f ⁇ )-f4aR*,7aS*)-6-f4-fdifluoromethyl)-5-fluoro-6-methoxypyrimidin-2- yl)-7a-f2-fluorophenyl)-4,4a,5.,6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2-amine
• Example 8 ( ⁇ )- - «4a ⁇ 7aS*)-2-amino-7a-q-fluorophenyl)-4a,5,7Ja- tetrahvdropyrrolo[3. l 4-dl [l. l 31thiazin-6f4H)-yl)-5-fluoro-6-methoxypyrimidin-4- vDmethanol
• reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (2 x 20 ml) then dried (MgS04) and evaporated to a brown foam (0.85 g) that contained rac-(2-((4aR*,7aS*)-2-benzamido- 7a-(2-fluorophenyl)-4a,5,7,7a-tetrahydrop
• Example 9 f ⁇ )-f4aR*,7aS*)-7a-f2-fluorophenyl)-6-f6-methoxy-4- ftrifluoromethyl)pyridin-2-yl)-4,4a,5. l 6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2- amine
• Example 11 f ⁇ )-f4aR*,7aS*)-7a-f2-fluorophenyl)-6-f6-methoxy-4- fmethoxymethyl)pyridin-2-yl)-4,4a,5.,6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2- amine
• tetrahydrofuran 50 ml at 0°C under nitrogen was added dropwise a solution of borane- tetrahydrofuran complex (1.0M solution in tetrahydrofuran; 40 ml) over fifteen minutes. After the addition was complete, the cooling bath was removed and the mixture allowed to warm to room temperature. After three hours, the mixture was cooled to 0°C and borane-tetrahydrofuran complex (1.0M solution in tetrahydrofuran; 40 ml) was added over fifteen minutes. After the addition was complete, the cooling bath was removed and the mixture allowed to warm to room temperature and stirred for seventeen hours.
• reaction mixture was cooled to 0°C, quenched with 1.0M aqueous sodium hydroxide solution (30 ml), diluted with saturated aqueous ammonium chloride solution (50 ml) and extracted with diethyl ether (2 x 100 ml), the combined organic layer washed with brine then dried (Na2SC"4) and evaporated. The residue was triturated with hexane and filtered to afford (2-chloro-6-methoxypyridin-4-yl)methanol (2.0 g) as a white solid.
• reaction mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (gradient from 0 to 50% ethyl acetate / hexane) to afford the title compound (0.039 g) as a white foam.
• Example 13 f ⁇ )-f4aR*,7aR*)-6-f5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-7a- fpyridin-2-yl)-4,4a,5. l 6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2-amine
• dichloromethane (20 ml) at -15°C was added a solution of benzoyl isothiocyanate (0.553 ml, 4.111 mmol) in dichloromethane (6.0 ml) and the reaction mixture stirred at - 15°C for ninety minutes. Solvent was removed in vacuo and the residue redissolved in dichloromethane and applied to a 20g SNAP KP-Si column.
• reaction mixture was quenched with sat. NaHC0 3 (aq) at -40°C before the reaction mixture was allowed to warm to RT.
• the layers were separated and the aqueous further extracted with DCM (x2).
• the combined organics were then washed with brine before being dried over MgSC"4, filtered and solvent removed in vacuo to afford the title compound (44 mg, 0.100 mmol, 100 % yield) as a yellow oil.
• Example 14 f4aR,7aR)-6-f5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-7a- fpyridin-2-yl)-4,4a,5. l 6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2-amine
• reaction mixture was stirred for seven hours, stored in the freezer at ⁇ -20°C for two days then poured into saturated aqueous ammonium chloride (100 ml), diluted with ethyl acetate (100 ml) and extracted. The organic layer was washed with brine then dried (MgSC"4) and evaporated and the residue was purified by silica gel column chromatography (gradient from 0% to 20% ethyl acetate / hexane) to afford the title compound (2.986 g) as a pale yellow oil.
• reaction mixture was diluted with ethyl acetate (50 ml) and washed with aqueous saturated sodium bicarbonate (2 x 25 ml) and aqueous saturated sodium chloride (25 ml) then dried (MgS04) and evaporated to afford the title compound (0.813 g) as a yellow foam.
• the reaction mixture was diluted with ethyl acetate (100 ml), washed with water (50 ml) and brine (50 ml) then dried (MgSC"4) and evaporated (Note: the aqueous was back extracted several times with dichloromethane).
• the residue was purified by silica gel column chromatography (gradient from 0 to 100% ethyl acetate / hexane followed by 5% methanol / ethyl acetate) to afford the title compound (0.613 g) as a pale yellow solid.
• N-((4aR,7aR)-6-(5-fluoro-4-methyl-6-oxo-l ,6- dihydropyrimidin-2-yl)-7a-(pyridin-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4- d][l,3]thiazin-2-yl)benzamide (0.61 g) in N,N-dimethylformamide (20 ml) was added potassium carbonate (0.27 g) followed by methyl iodide (0.082 ml) in N,N- dimethylformamide (5 ml) and the mixture stirred at room temperature for one hour.
• reaction mixture was diluted with ethyl acetate (250 ml), washed with water (2 x 50 ml and 100 ml) then dried (MgS04) and evaporated.
• the residue was purified by silica gel column chromatography (gradient from 0 to 50% ethyl acetate / hexane) to afford the title compound (0.343 g) as a white foam.
• reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3 x 50 mL) then dried (MgS0 4 ) and evaporated. The residue was dissolved in dichloromethane and applied to a 25g SNAP KP-Si column. Purified on the Biotage Isolera 4 eluting with 0 to 30% ethyl acetate / hexane over 10 column volumes to afford the title compound (0.488 g) as a white foam.
• Example 17 ( ⁇ )- (4aR*,7aS*)-7a- ,4-difluorophenyl)-6-(5-fluoro-4-methoxy-6- methylpyrimidin-2-yl)-4,4a,5.,6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2-amine
• Example 18 ( ⁇ )-( 4aR*,7aR*)-6-( 5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-7a- fthiophen-l-vD ⁇ a ⁇ ⁇ a-hexahvdropyrroloiS ⁇ -dl il lthiazin-l-amine
• Benzoyl isothiocyanate (3.72 mL, 27.7 mmol) was added dropwise to a solution ( ⁇ )-(3R*,4R*)-tert-butyl 3-amino-4-(hydroxymethyl)-3-(thiophen-2-yl)pyrrolidine-l- carboxylate (6.35 g, 21.3 mmol) in DCM (37 mL). The reaction was stirred at r.t. for 2h and was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient from 20% to 60% EtOAc in Hexanes) to afford the title compound as a colorless foam (8.18 g, 83%> over 2 steps).
• the reaction was stirred at r.t. for 2h and at reflux for 2h.
• the reaction mixture was diluted with EtOAc and saturated aqueous NaHC0 3 solution.
• the two layers were separated and the aqueous phase extracted with EtOAc (x2).
• the combined organic extracts were washed with brine, dried over Na 2 S0 4 and concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (gradient from 60% to 100% EtOAc in Hexanes) to give the desired product as a colorless foam (3.27g, 75%> over 2 steps).
• Example 20 ( ⁇ )-( 4aR*,7aR*)-7a-cvclopentyl-6-( 5-fluoro-4-methoxy-6- methylpyrimidin-2-yl)-4,4a,5. l 6. l 7. l 7a-hexahvdropyrrolo[3. l 4-dl [l. l 31thiazin-2-amine
• the combined organic extracts were dried over MgS0 4 and evaporated to give an oil (8.24 g).
• the oil was purified by silica gel chromatography, collecting fractions containing molecular weight 282 on LCMS analysis, to afford a crude sample presumed to contain 20-(l) (3.30 g).
• the oil was dissolved in THF (20 mL) and acetic acid (2 mL) was added, followed by zinc powder (1.00 g). After stirring vigorously for 16 h, the mixture was filtered through celite, washing with MeOH (100 mL). The filtrate was evaporated and NaHC0 3 (sat., aq., 50 mL) was added.
• Example 21 f ⁇ )-f4aR*,7aR*)-6-f5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-7a- ( tetrahydro-2H-pyran-4-yl)-4,4a,5,6,7 a-hexahydropyrrolo [3,4-dl [ 1 ,31 thiazin-2- amine
• Tetrahydro-2H-pyran-4-carboxylic acid (3 g, 23.052 mmol) was dissolved in dry DCM (20 mL) and one drop of DMF added. The reaction mixture was cooled to 0°C before Oxalyl chloride (2.212 ml, 25.357 mmol) was added dropwise and the reaction mixture stirred at rt under nitrogen for 2 hours. Solvent was removed in vacuo after this time, before the residue was redissolved in DCM (20 mL) and the resulting solution was added dropwise to a solution of Trimethylsilyldiazomethane (20.75 ml, 41.493 mmol) (2M in hexane) at -10°C.

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